Contribution of plasma proteins, albumin and alpha 1-acid glycoprotein, to pharmacokinetics of a multi-targeted receptor tyrosine kinase inhibitor, sunitinib, in analbuminemic rats

Abstract

The present study investigated the role of the major plasma proteins, albumin and α1-acid glycoprotein (AAG), in the pharmacokinetics of sunitinib using Sprague-Dawley (SD) rats and analbuminemic rats with considerably low concentration of albumin established from SD rats. When sunitinib (3 mg/kg) was administered intravenously, the plasma concentrations of sunitinib at the early-distribution phase were significantly lower in analbuminemic rats than those in SD rats. The corresponding pharmacokinetic parameters of systemic clearance and volume of distribution at steady-state of sunitinib were significantly larger in analbuminemic rats (2.17 l/h/kg and 3.94 l/kg, respectively) than those in SD rats (1.26 l/h/kg and 2.37 l/kg, respectively). In in vitro protein-binding experiments using an equilibrium dialysis method, the binding profiles of sunitinib in SD and analbuminemic rats were linear, and the unbound fraction in analbuminemic rats (0.110) was significantly larger than that of SD rats (0.062). However, no significant differences in the unbound plasma concentration-time curves and pharmacokinetic parameters of sunitinib were observed between SD and analbuminemic rats. Protein-binding profiles of sunitinib to human serum albumin and AAG showed concentration independency and the binding potency was 65.3% and 33.7%, respectively. These results suggest that AAG has a low affinity for sunitinib and that the contribution of AAG to plasma protein-binding of sunitinib is relatively low compared to albumin. The present study suggests that the increased systemic clearance of sunitinib in analbuminemic rats might be due to an increase in the volume of distribution at steady-state, which could be due to the significant increase in the unbound fraction of sunitinib due to the low concentration of albumin.

Keywords: Sunitinib; albumin; pharmacokinetics; protein-binding profiles; α1-acid glycoprotein (AAG).